Abstract Brucellosis is the most common zoonotic disease worldwide. Although rarely fatal in humans, brucellosis can be severely debilitating disease causing relapses of an undulating fever and lifelong problems, including arthritis, spondylitis, sacroiliitis, endocarditis, and possible neurological complications. The elimination of infected livestock combined with vaccination of seronegative animals has effectively reduced the incidence of human brucellosis in many countries. However, brucellosis remains problematic in countries in Central and South America, the Middle East, Mediterranean rim, Africa, and Eastern and Central Asia where many infected animals remain. To date, there are no effective vaccines for humans, and because of limited efficacy of conventional vaccines for livestock, such threat makes it difficult and costly to eradicate the disease. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure, and ultimately results in a systemic disease. Only few studies have considered the mucosal aspects of Brucella's pathogenesis. Given the relevance of mucosal exposure for Brucella infection, a vaccine devised at immunizing the oropharyngeal mucosa and associated lymphoid tissues has a high potential of success. In a quest to develop a more efficacious vaccine, several live attenuated Brucella mutants were generated, and when given mucosally, they confer complete protection against virulent Brucella challenges. Although mice have long been instrumental in our understanding of immunity to Brucella, infections need to be studied in animals that are natural hosts for Brucella, and one that share both physiological and immunological traits with humans. Hence, we seek to develop an animal model that reflects human brucellosis. Domestic, pigs' close resemblance to human immune system and anatomy of the oropharyngeal mucosa will allow us to study mucosal aspects of brucellosis in a natural host. The proposed work will investigate whether pigs can be adapted as a surrogate model to define the tenets of protective immunity subsequent oropharyngeal vaccination. Studies in Specific Aim 1 will determine the best oral vaccination regimen using our attenuated Brucella mutants. Studies in Specific Aim 2 will define which innate and adaptive cells induced in the oropharyngeal lymphoid tissues by oral vaccination to learn the source of the IFN- ?- and other cytokine-producing cells needed to resolve Brucella infections. Upon conclusion of these studies, we will establish an animal model for human brucellosis to enable future testing of brucellosis vaccines.